Abstract
Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" ≥ 30 kg/m2) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1+CD8+ T cells, CD14+CD16neg classical monocytes, and Foxp3+ regulatory T cells (Tregs). Only CD14+CD16neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ+ CD8 T cells or IFNγ+, IL-4+, or IL-17A+ CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1β, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI ≥ 35 kg/m2 versus 18.5-24.9 kg/m2, respectively) subjects. Intratumoral PLGF and VEGF-A proteins were elevated in ccRCC subjects with obesity. Thus, in ccRCC patients with localized disease, obesity is not associated with widespread detrimental alterations in systemic or intratumoral immune profiles. The effects of combined obesity and immunotherapy administration on immune parameters remains to be determined.
Highlights
Renal and pelvic cancers are among the ten most common cancers in the United States, with over 65,000 cases diagnosed in 2018 alone and approximately 23% resulting in fatality [1]
Our study has provided what we believe to be the first in-depth evaluation of the effects of obesity on systemic and tumor immune profiles of clear cell renal cell carcinoma (ccRCC) patients
Our study has limitations, including the relatively small cohort size, limited probe availability precluding indepth or high-throughput flow cytometric analysis, lack of spatial and interactive evaluation of tumor-infiltrating leukocyte populations, the restriction of our gene expression analysis to only immune-related genes, the fact that all subjects were consented from one institution in a state with a predominantly Caucasian-American demographic composition, and the relatively limited number of female subjects, which precluded our ability to determine if biological sex leads to variations in the immune parameters we examined here
Summary
Renal and pelvic cancers are among the ten most common cancers in the United States, with over 65,000 cases diagnosed in 2018 alone and approximately 23% resulting in fatality [1]. Multiple subtypes of renal cancer exist, but clear cell renal cell carcinoma (ccRCC) accounts for nearly 75% of cases [2]. Objective response rates to CPI biologics remain < 50% in RCC patients [4], even when used in combination [5]. For this reason, intense efforts are underway to identify the underlying causes of suboptimal CPI efficacy
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